Abstract
We assessed the association of vascular endothelial growth factor (VEGF) and nml23 expression with occult micrometastasis in lung cancer. As destination sites for micrometastasis, we scrutinized lymph node (LN) and bone marrow (BM) specimens. For LN, 122 stage I patients who had received curative operations were studied. As regards BM, 203 patients in stage I‐IV who underwent operations were registered. Immunohistochemical anti‐cytokeratin staining was used to detect microdissemination of cancer cells. The VEGF and the nm23 expression at the primary sites were immunohistochemically studied in 285 cases in total. The percentages of the patients with micro‐dissemination were 28.7% for LN and 42.4% for BM. The outcome for the patients with LN or BM microdissemination was significantly worse than that for patients without it. The increased VEGF and the decreased nm23 expression within primary tumors were significantly associated with LN and BM microdissemination. The results indicate possible value of using these biological markers to predict the risk of systemic micrometastasis in non‐small cell lung cancer.
Keywords: VEGF, nm23, Lung cancer, Micrometastasis, Recurrence
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References
- 1.Ohta , Y. , Endo , Y. , Tanaka , M. , Shimizu , J. , Oda , M. , Hayashi , Y. , Watanabe , Y. . and Sasaki , T.Significance of vascular endothelial growth factor messenger RNA expression in primary lung cancer . Clin. Cancer Res. , 2 , 1411 – 1416 ( 1996. ). [PubMed] [Google Scholar]
- 2.Ohta , Y. , Tomita , Y. , Oda , M. , Watanabe , S. , Murakami , S. . and Watanabe , Y.Tumor angiogenesis and recurrence in stage I non‐small cell lung cancer . Ann. Thorac. Surg. , 67 , 1034 – 1038 ( 1999. ). [DOI] [PubMed] [Google Scholar]
- 3.Gabrilovich , D. I. , Chen , H. L. , Girgis , K. R. , Cunningham , H. T. , Meny , G. M. , Nadaf , S. , Kavanaugh , D. . and Carbone , D. P.Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells . Nat. Med. , 2 , 1096 – 1103 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 4.Skobe , M. , Rockwell , P. , Goldstein , N. , Vosseler , S. . and Fusenig , N. E.Holting angiogenesis suppresses carcinoma cell invasion . Nat. Med. , 3 , 1222 – 1227 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 5.Herold‐Mende , C. , Steiner , H. , Addl , T. , Riede , D. , Buttler , A. , Reisser , C. , Fusenig , N. E. . and Mueller , M. M.Expression and functional significance of vascular endothelial growth factor receptors in human tumor cells . Lab. Invest ., 79 , 1573 – 1582 ( 1999. ). [PubMed] [Google Scholar]
- 6.Arbiser , J. L. , Larsson , H. , Claesson‐Welsh , L. , Bai , X. , LaMontagne , K. , Weiss , S. W. , Soker , S. , Flynn , E. . and Brown , L. F.Overexpression of VEGF 121 in immortalized endothelial cells causes conversion to slowly growing angiosarcoma and high level expression of the VEGF receptors VEGFR‐1 and VEGFR‐2 in vivo . Am. J. Pathol , 156 , 1469 – 1476 ( 2000. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Baek , J. H. , Jang , J. , Kang , C. , Chung , H. , Kim , N. D. and Kim , K.Hypoxia‐induced VEGF enhances tumor surviv‐ability via suppression of serum deprivation‐induced apo‐ptosis . Oncogene , 19 , 4621 – 4631 ( 2000. ). [DOI] [PubMed] [Google Scholar]
- 8.Brans , C. J. , Liu , W. , Davis , D. W. , Shaheen , R. M. , McConkey , D. J. , Wilson , M. R. , Bucana , C. D. , Hicklin , D. J. . and Ellis , L. M.Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal carcinoma liver metastases . Cancer , 89 , 488 – 499 ( 2000. ). [PubMed] [Google Scholar]
- 9.Huvos , A. G. , Hutter , R. V. and Berg , J. W.Significance of axillary macrometastases and micrometastases in mammary cancer . Ann. Surg. , 173 , 44 – 46 ( 1971. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Izbicki , J. R. , Passlick , B. P. , Hosch , S. B. , Kubuschock , B. , Schneider , C. , Busch , C. , Knoefel , W. T. , Thetter , O . and Pantel , K.Mode of spread in the early phase of lymphatic metastasis in non‐small‐cell lung cancer: significance of nodal micrometastasis . J. Thorac. Cardiovasc. Surg. , 112 , 623 – 630 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 11.Ohta , Y. , Nozawa , H. , Tanaka , Y. , Oda , M . and Watanabe , Y.Increased vascular endothelial growth factor and vascular endothelial growth factor‐c and decreased nm23 expression associated with microdissemination in the lymph nodes in stage I non‐small cell lung cancer . J. Thorac. Cardiovasc. Surg. , 119 , 804 – 813 ( 2000. ). [DOI] [PubMed] [Google Scholar]
- 12.Royds , J. A. , Stephenson , T. J. , Rees , R. C. , Shorthouse , A. J. . and Silicocks , P. B.Nm23 protein expression in ductal in situ and invasive human breast carcinoma . J. Natl. Cancer Inst. , 85 , 727 – 731 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 13.Redding , W. H. , Coombes , R. C. , Monaghan , P. , Clink , H. , Imrie , S. F. , Dearnaley , D. P. , Ormerod , M. G. , Sloane , J. P. , Gazet , J. C. , Powles , T. J. . and Neville , A. M.Detection of micrometastases in patients with primary breast cancer . Lancet , ii , 1271 – 1274 ( 1983. ). [DOI] [PubMed] [Google Scholar]
- 14.Pantel , K. , Izbichi , J. R. , Angstwurm , M. , Braun , S. , Passlick , B. , Karg , O. , Thetter , O. . and Riethmuller , G.Immunocytological detection of bone marrow micrometastasis in operable non‐small cell lung cancer . Cancer Res. , 53 , 1027 – 1031 ( 1993. ). [PubMed] [Google Scholar]
- 15.Cote , R. J. , Beattie , E. J. , Chaiwun , B. , Shi , S. R. , Harvey , J. , Chen , S. C. , Sherrod , A. E. , Groshen , S. . and Taylor , C. R.Detection of occult bone marrow micrometastases in patients with operable lung carcinoma . Ann. Surg. , 222 , 415 – 423 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Pantel , K. , Izbicki , J. , Passlick , B. , Augstwurm , M. , Haussinger , K. , Thetter , O. . and Riethmuller , G.Frequency and prognostic significance of isolated tumour cells in bone marrow of patients with non‐small‐cell lung cancer without overt metastases . Lancet , 347 , 649 – 653 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 17.Izbicki , J. R. , Passlick , B. , Hosch , S. B. , Kubuschock , B. , Schneider , C. , Busch , C. , Knoefel , W. T. . and Thetter , O.Mode of spread in the early phase of lymphatic metastasis in non‐small‐cell lung cancer: significance of nodal micrometastasis . J. Thorac. Cardiovasc. Surg. , 112 , 623 – 630 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 18.Ohta , Y. , Watanabe , Y. , Murakami , S. , Oda , M. , Hayashi , Y. , Nonomura , A. , Endo , Y. . and Sasaki , T.Vascular endothelial growth factor and lymph node metastasis in primary lung cancer . Br. J. Cancer , 76 , 1041 – 1045 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Fontanini , G. , Boldrini , L. , Chine , S. , Pisaturo , F. , Basolo , F. , Calcinai , A. , Lucchi , M. , Mussi , A. , Angeletti , C. A. . and Bevilacqua , G.Expression of vascular endothelial growth factor mRNA in non‐small‐cell lung carcinomas . Br. J. Cancer , 79 , 363 – 369 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Yuan , A. , Yu , C. J. , Luh , K. T. , Chen , W. T. , Lin , F. Y. , Kuo , S. H. . and Yang , P. C.Quantification of VEGF mRNA expression in non‐small cell lung cancer using a real‐time quantitative reverse transcription‐PCR assay and a comparison with quantitative competitive reverse transcription‐PCR . Lab. Invest. , 80 , 1671 – 1680 ( 2000. ). [DOI] [PubMed] [Google Scholar]
- 21.Marone , M. , Scambia , G. , Ferrandina , G. , Giannitelli , C. , Benedetti‐Panici , P. , Lacovella , S. , Leone , A. . and Mancuso , S.Nm23 expression in endometrial and cervical cancer: inverse correlation with lymph node involvement and myo‐metrial invasion . Br. J. Cancer , 74 , 1063 – 1068 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Kawakubo , Y. , Sato , Y. , Koh , T. , Kono , H. . and Kameya , T.Expression of nm23 protein in pulmonary adenocarcinomas: inverse correlation to tumor progression . Lung Cancer , 17 , 103 – 113 ( 1997. ). [DOI] [PubMed] [Google Scholar]
- 23.Sauer , T. , Furu , L , Beraki , K. , Jebsen , P. W. , Ormerod , E. . and Naess , O.Nm23 protein expression in fine‐needle aspirates from breast carcinoma: inverse correlation with cytologic grading, lymph node status, and ploidy . Cancer , 84 , 109 – 114 ( 1998. ). [PubMed] [Google Scholar]
